Cyclodextrin/drug complexes are typically formed prior to their use in pharmaceutical formulations. U.S. Pat. No. 5,134,127 (the '127 Patent) to Stella et al. relates to sulfoalkyl ether cyclodextrin (SAE-CD) derivatives. The SAE-CD derivatives are proposed to be used as solubilizing agents for poorly water soluble or water insoluble drugs in various pharmaceutical dosage forms. The '127 Patent relates to compositions and formulations containing a drug complexed to a SAE-CD derivative to form clathrate/drug complexes or inclusion complexes thereof. Pharmaceutical formulations contemplated therein relate to those that include the clathrate complex and a pharmaceutically acceptable carrier. All of the formulations disclosed in the '127 patent require the preformation of an Drug/SAE-CD complex prior to preparation of the formulation.
Cyclodextrin (CD)/drug clathrate complexes are generally prepared separately prior to placement in a desired pharmaceutical formulation. Processes to prepare such formulations include steps that require much process monitoring and control and as such may complicate the formulation process. Efforts have been made to formulate cyclodextrins with poorly water soluble drugs together as physical mixtures and as inclusion complexes. Muranushi et al. (Nippon Yakurigaky Zasahi (1988), 91(6), 377-383) compared the dissolution profiles for neat benexate, benexate/cyclodextrin physical mixture and benexate-cyclodextrin complex. They reported the significantly increased solubility of benexate when prepared in the complexed vs. physical mixture or neat forms.
Similar results were reported by J. J. Torres-Labandeira et al. (STP Pharma. Sci. (1994), 4(3), 235-239) wherein the bioavailability of glibomuride-.beta.-cyclodextrin complex was found to be two to three fold better than that of the glibomuride/.beta.-cyclodextrin physical mixture. D. Peri et al. (Drug. Dev. Ind. Pharm. (USA) (1994), 20(4) 1401-1410) also reported that the drug-.beta.-cyclodextrin complex showed improved dissolution over the physical mixture or free drug for tolnaftate. When naproxen and .beta.-cyclodextrin were tested, the respective inclusion complex was found to have a six to nine fold increased solubility at five minutes over that of the physical mixture. (Otero-Espinar et al., Int. J. Pharm. (Netherlands) (1991), 75(1), 37-44).
Further evidence that the drug-.beta.-cyclodextrin inclusion complex generally possesses a significantly better, dissolution profile than the corresponding physical mixture was reported by Lin et al. (Int. J. Pharm. (Netherlands) (1989), 56(3), 249-259) when .beta.-cyclodextrin complexes and physical mixtures of acetaminophen, indomethacin, piroxicam and warfarin were tested. Esclusa-Diaz et al. (Int. J. Pharm. (Netherlands) (1996), 142(2) 183-187) also reported that the ketoconazole-.beta.-cyclodextrin complex had a significantly better solubility than the corresponding physical mixture.
U.S. Pat. No. 4,946,686 to McClelland et al. discloses but does not exemplify another application of drug/cyclodextrin physical mixtures. This composition was designed solely for controlled release of a drug wherein solubility modulating units were present as slow release particles dispersed throughout a mixture of drug excipients. All of the components were then surrounded by a microporous water insoluble wall.
Okimoto et al. (Pharmaceutical Research, (1998) 15(10), 1562-1568), disclose an osmotic pump tablet containing prednisolone which is a poorly water soluble drug and the SAE-CD (SBE).sub.7M -.beta.-CD. The osmotic pump tablet is prepared by kneading prednisolone and the cyclodextrin in the presence of water resulting in complexation of a significant portion, if not a major portion, of the prednisolone. A core containing the drug and cyclodextrin is coated with a semipermeable membrane containing a pore former to provide the osmotic pump tablet. The reported results indicate that a sustained release profile is provided by the osmotic pump tablet so long as the semipermeable membrane is present. Okimoto et al. further disclose that the SAE-CD can be used as a solubilizing agent and as an osmotic agent.
Giunchedi et al. (J. Pharm. Pharmacol., (1994), 46. 476-480), disclose the preparation of a zero order release formulation containing the water insoluble drug naftazone .beta.-cyclodextrin and hypromellose. The method of preparing this formulation resulted in the formation of a significant amount of preformed drug/cyclodextrin complex which measurably altered the morphology and characteristics of both the drug and the cyclodextrin.
Chino et al. (Proceed. Intern. Symp. Control Rel. Bioact. Mater., (1992) 19. 98-99) disclose the preparation of a sustained release formulation containing a drug, a cyclodextrin and a hydrogel wherein the cyclodextrin and hydrogel were either conjugated together or mixed together prior to formation of the final formulation. In each example, the drug 5-FU was complexed with the cyclodextrin moiety during preparation of the formulation.
Mura et al. (Pharm. Acta Helv., (1992) 67(9-10), 282-288) disclose formulations incorporating methyl .beta.-cyclodextrin in combination with clonazepam into a solid composition wherein the drug and cyclodextrin are either complexed or uncomplexed prior to being dispersed or dissolved in a gel matrix. Mura et al. report that the methyl-.beta.-cyclodextrin improves the flux rate of clonazepam from these gels through a lipophilic membrane comprising cellulose nitrate impregnated with lauryl alcohol.
Uekama et al. (J. Pharm. Sci., (1990), 79(3n): 244-248) disclose a slow release dosage form of piretanide which is a bi-layered tablet having a first rapid releasing layer and a second slow releasing layer wherein the first rapidly releasing layer comprises .beta.-cyclodextrin complexed with the piretanide.
Corrigan and Stanley (Pharm. Acta Helv. (1981) 56(7): 204-208) disclose controlled release formulations comprising phenobarbitone and .beta.-cyclodextrin as eiter a preformed complex or physical mixture. Corrigan and Stanley report that the preformed complex performs substantially better than the physical mixture in terms of providing a reasonable controlled dissolution of the drug.
Martini (Proceed. Intern. Symp. Control. Rel. Bioact. Mater., (1993), 20: 304-305 disclose the use of .beta.-cyclodextrin to improve the bioavailability of drugs having a very low water solubility but a good absorption rate through biological membranes. The Martini formulation comprises a physical mixture of the .beta.-cyclodextrin with the drug temazepam as either a physical mixture or preformed complex. In only one of several examples did Martini et al. obtain a physical mixture formulation having a dissolution profile comparable to that of the preformed complex formulation.
Elger et al. in European Patent Application Ser. No. 251,459 A discloses a controlled release pharmaceutical composition which comprises a drug, a water-soluble polydextrose or cyclodextrin, and a fatty alcohol or polyalkylene glycol wherein the drug and cyclodextrin can be present as a physical mixture or inclusion complex.
Thus, the art teaches that a drug-cyclodextrin preformed complex will generally have significantly better solubility, dissolution profile and bioavailability than its respective physical mixture. In the pharmaceutical industry, simplified processes are preferred over complex ones, and, with regard to cyclodextrin-containing and, specifically, SAE CD-containing compositions, a need continues to exist for simplified compositions and processes for their preparation. A need continues to exist in the pharmaceutical arts for a pharmaceutical formulation containing a drug/cyclodextrin physical mixture that possesses a dissolution profile, bioavailability and solubility similar to those characteristic of the respective drug-cyclodextrin complex.